N-(aroyl)glycine hydroxamic acid derivatives and related compounds

ABSTRACT

Compounds&#39; of formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , AA and Y are as defined herein, inhibit phosphodiesterase type IV or inhibit the production of tumor necrosis factor, and therefore are useful in the treatment of certain conditions and diseases including asthma, arthritis, and sepsis.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to N-(aroyl)glycine hydroxamic acid derivatives and related compounds that are selective inhibitors of phosphodiesterase (PDE) type IV or of the production of tumor necrosis factor (TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases as well as AIDS, sepsis, septic shock, cachexia, and other diseases involving the production of TNF. The compounds of this invention may have combined PDE type IV and TNF inhibitory activity. The present invention also relates to the use of such compounds in the treatment of the above diseases in mammals, particularly humans, and to pharmaceutical compositions useful therefor.

[0002] Since the recognition that cyclic AMP is an intracellular second messenger (E. W. Sutherland, and T. W. Rail, Pharmacol. Ref., 1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized (J. A. Beavo and D. H. Reifsnyder, TIPS, 1990, 11, 150), and their selective inhibition has led to improved drug therapy (C. D. Nicholson, R. A. Challiss and M. Shahid, TIPS, 1991, 12, 19). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M. W. Verghese et al., J. Mol. Cell Cardiol., 1989, 12, (Suppl. II), S 61) and airway smooth muscle relaxation (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.

[0003] TNF is recognized to be involved in many infectious and auto-immune diseases, including cachexia (W. Friers, FEBS Letters, 1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al., Clinical Immunology and Immunopatholoty, 1992,62, S 11).

SUMMARY OF THE INVENTION

[0004] The invention relates to compounds of formula

[0005] or a pharmaceutically acceptable salt thereof,

[0006] wherein R¹ is selected from the group consisting of methyl, ethyl, difluoromethyl and trifluoromethyl;

[0007] R² is (C₁-C₆)alkyl, (C₃-C₇)alkoxy(C₂-C₄)alkyl, phenoxy(C₂-C₈)alkyl, (C₃-C₇)cycloalkyl, (C₈-C₉)polycycloalkyl, phenyl(C₁-C₈)alkyl or indanyl wherein the alkyl portion of said R² groups is optionally substituted with one or more fluorine atoms and the aromatic portion of said R² groups is optionally substituted with one or more substituents independently selected from the group consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy and halogen;

[0008] AA is (AA-1) or (AA-2) wherein:

[0009] (AA-1) is

[0010]  wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, trifluoromethyl, (C₁-C₆)alkyl, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CONH₂, —(CH₂)_(n)phenyl, —(CH₂)_(x)OH, and —(CH₂)_(x)NH₂, wherein x ranges from 1 to 5, n ranges from 0 to 5, R⁵ is hydrogen, OH or (C₁-C₆)alkyl, and m ranges from 0 to 5; and,

[0011] (AA-2) is

[0012]  wherein p ranges from 1 to 4; and,

[0013] Y is NHOH or OH.

[0014] The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.

[0015] The term “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.

[0016] The term “cycloalkyl”, as used herein, includes saturated monovalent cyclo hydrocarbon radicals including cyclobutyl, cyclopentyl and cycloheptyl.

[0017] The term “polycycloalkyl”, as used herein, includes saturated monovalent polycyclo radicals comprising ring assemblies that are fused, bicyclo or tricyclo. Such ring assemblies include bicycloheptyl, bicyclobutyl, tricyclooctanyl and perhydropentalenyl.

[0018] The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy and (C₁-C₆)alkyl.

[0019] The term “treatment” as used herein, unless otherwise indicated, includes (i) methods to cure, relieve or lessen the undesirable effects of, or the undesirable symptoms associated with, conditions and diseases that respond to the inhibition of PDE type IV or the inhibition of the production of TNF, where such conditions and diseases are actively occurring in a mammal, including a human, and (ii) methods to prevent such conditions and diseases from occurring in a mammal, and (iii) methods to slow the onset of such conditions and diseases in a mammal. The terms “treat” and “treating” as used herein are defined in accord with the above definition.

[0020] The term “therapeutically effective amount” as used herein, unless otherwise indicated, means an amount effective to inhibit PDE type IV or inhibit the production of TNF, or an amount effective in the treatment, as defined above, of a condition or disease that responds to the inhibition of PDE type IV or the inhibition of the production of TNF.

[0021] The compounds of formula I include certain compounds having chiral centers which therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.

[0022] Preferred compounds of formula I include those in which R¹ is methyl.

[0023] Other preferred compounds of formula I include those in which R² is cyclopentyl.

[0024] Other preferred compounds of formula I include those in which AA is the moiety (i) and R³ is hydrogen, methyl, trifluoromethyl or —CH₂OH.

[0025] Other preferred compounds of formula I include those in which AA is the moiety (AA-1) and R⁴ is hydrogen.

[0026] Other preferred compounds of formula I include those in which AA is the moiety (AA-1) and R⁵ is hydrogen.

[0027] Other preferred compounds of formula I include those in which AA is the moiety (AA-1) and m is 0.

[0028] Other preferred compounds of formula I include those in which Y is —NHOH.

[0029] Specific preferred compounds of formula I include the following:

[0030] α-monofluoromethyl-α-N-[(3cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;

[0031] α-difluoromethyl-α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;

[0032] α-ethyl-α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;

[0033] α-propyl-α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;

[0034] α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]-D-cystine hydroxamic acid;

[0035] α-trifluoromethyl-α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;

[0036] α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]-D-serine hydroxamic acid;

[0037] α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid; and,

[0038] α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]-D-alanine hydroxamic acid.

[0039] The present invention further relates to a pharmaceutical composition for the inhibition of PDE type IV or the inhibition of the production of TNF in a mammal, including a human, comprising a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0040] The present invention further relates to a pharmaceutical composition for the treatment of a condition or disease selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis, AIDS, septic shock and other conditions or diseases that respond to the inhibition of PDE type IV or the inhibition of the production of TNF in a mammal, including a human, comprising a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0041] The present invention further relates to a method of inhibiting PDE type IV or inhibiting the production of TNF in a mammal, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.

[0042] The present invention further relates to a method of treating a condition or disease selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis, AIDS, septic shock and other conditions or diseases that respond to the inhibition of PDE type IV or the inhibition of TNF in a mammal, including a human, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0043] The following reaction Scheme 1 illustrates the preparation of the compounds of the present invention. Unless otherwise indicated, R¹, R², R³, R⁴, R⁵, AA, n, m, p, and Y, as used in Scheme 1 and the following discussion, are as defined above. In Scheme 1 and the Preparations and Examples that follow, all synthesis reactions and other procedures are done at room temperature (20-25° C.) unless otherwise indicated.

[0044] In reaction 1 of Scheme 1, a carboxylic acid of formula V is coupled to O-benzylhydroxylamine to obtain a compound of formula VI using a coupling method well known to those skilled in the art of peptide chemistry. The carboxylic acid of formula V is available from various commercial sources or can be prepared according to synthetic methods known to those skilled in the art. The preferred coupling method is to combine the compound of formula V with O-benzylhydroxylamine hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base, such as triethylamine, in an inert solvent, such as methylene chloride, at a temperature of 0° C. to 30° C. (20-25° C. preferred) for a period of 2 hours to 48 hours (16 hours preferred).

[0045] In reaction 2 of Scheme 1, the compound of formula VI is treated with an acid, such as hydrochloric acid or trifluoroacetic acid, to remove the t-butyloxycarbonyl group to give a salt of formula VII, wherein X of HX is chloride or trifluoroacetate, and m, R³, R⁴ and R⁵ are as defined above.

[0046] In reaction 3 of Scheme 1, the salt of formula VII is coupled to a benzoic acid derivative of formula VIII to prepare the compound of formula IX using a coupling method well known to those skilled in the art of peptide chemistry. The benzoic acid derivative of formula VIII can be prepared according to synthetic methods known to those skilled in the art. For instance, 3-cyclopentyloxy-4-methoxybenzoic acid can be prepared according to the method described in M. N. Palfreyman et al., J. Med. Chem., vol. 37, page 1696 (1994), which is herein incorporated by reference. The preferred coupling method is to combine the compound of formula VIII with the salt of formula VII, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base, such as triethylamine, in an inert solvent, such as methylene chloride, at a temperature of 0° C. to 30° C. (20-25° C. preferred) for a period of 2 hours to 48 hours (16 hours preferred).

[0047] In reaction 4 of Scheme 1, the compound of formula IX is hydrogenated over Pd(OH)₂ in a solvent such as methanol or ethanol for a period of 4 to 48 hours (16 hours preferred) to obtain the compound of formula X.

[0048] While Scheme 1 illustrates the preparation of compounds of formula I wherein AA is (AA-1), the preparation of compounds of formula I wherein M is (AA-2) follows essentially the same route. In particular, in the first step, the compound of formula V is replaced with a compound of the same formula except the AA portion is (AA-2) rather than (AA-1). Such compounds are commercially available or can be made by synthetic techniques known to those skilled in the art. Then, reactions 1-4 are performed as described above.

[0049] To prepare compounds of formula I wherein Y is OH rather NHOH, the process begins at the third reaction of Scheme 1 where the compound of formula VII is replaced with a compound of formula XI: HX.NHR⁵CR³R⁴(CH₂)_(m)CO₂CH₂Ph. Compounds of formula XI are commercially available or can be made by synthetic techniques known to those skilled in the art. The compound of formula XI is coupled with the compound of formula VIII as described above for reaction 3 of Scheme 1. Then, reaction 4 of Scheme 1 is followed as described above to prepare the compound of formula I wherein Y is OH.

[0050] Pharmaceutically acceptable acid addition salts of the compounds of this invention include, but are not limited to, those formed with acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, toluenesulfonic, mandelic, di-p-toluoyl-L-tartaric and related acids. The acid addition salts of the compounds of formula I are prepared in a conventional manner by treating a solution or suspension of the free base of formula I with about one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration or crystallization techniques are employed in isolating the salts. Pharmaceutically acceptable cationic salts of the compounds of formula I wherein Y is hydroxyl include, but are not limited to, those of sodium, potassium, calcium, magnesium, ammonium, N,N′-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine and diethanolamine.

[0051] The ability of the compounds of formula I and their pharmaceutically acceptable salts to inhibit PDE type IV or inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases that respond to the inhibition of PDE IV or the inhibition of the production of TNF is shown by the following in vitro assay tests.

BIOLOGICAL ASSAY Human Eosinophil PDE

[0052] Human peripheral blood is collected in ethylenediaminetetraacetic acid, diluted 1:2 in piperazine-N,N′-bis-2-ethanesulfonic acid (PIPES) buffer and then layered over percoll solution. Gradients are formed by centrifugation for 30 minutes at 2000 rpm at 4° C. The remainder of the isolation procedure, which is based on the procedure of Kita et al., J. Immunol., 152, 5457 (1994), is carried out at 4° C. The neutrophil/eosinophil layer is collected from the percoll gradient and the red blood cells are lysed. Remaining cells are washed in PIPES (1% FCS), incubated with anti-CD16 microbeads (MACS) for 1 hour, and passed over a magnetic column to remove the neutrophils. Eosinophils are collected in the eluate and analyzed for viability by trypan blue and purity by diff-quick stain. Eosinophil purity is routinely greater than 99% using this method.

[0053] Purified eosinophils are resuspended in 750 μL of PDE lysis buffer (20 mM triethylamine, 1 mM ethylenediaminetetraacetic acid, 100 μg/ml bacitracin, 2 mM benzamidine, 50 μM leupeptin, 50 μM PMSF, 100 μg/ml soybean trypsin inhibitor) and quick frozen in liquid nitrogen. Cells are thawed slowly and sonicated. Membranes are vortexed (disruption is confirmed by Trypan blue staining of fragments). Disrupted cells are centrifuged at 45 k rpm for 30 minutes at 4° C. to isolate membranes. Cytosol is decanted, and membrane resuspended to 200 μg/ml for use as PDE source in the hydrolysis assay yielding a window from 3000 to 5000 counts.

[0054] Compounds are dissolved in dimethyl sulfoxide at 10-2M, then diluted 1:25 in water to 4×10⁻⁴ M. This suspension is serially diluted 1:10 in 4% dimethyl sulfoxide, for a final dimethyl sulfoxide concentration in the assay of 1%.

PHOSPHODIESTERASE INHIBITION ASSAY

[0055] To 12×75 mm glass tubes add:

[0056] 25 μl PDE assay buffer (200 mM Tris/40 mM MgC12)

[0057] 24 μl 4 nM/ml cAMP stock

[0058] 25 μl test compound

[0059] 25 μl PDE source (membrane)

[0060] Background control=membrane boiled 10″

[0061] Positive control—25 μl unboiled membrane

[0062] Incubate 25 minutes in 37° C. water bath.

[0063] Reaction is stopped by boiling samples 5 minutes. Samples are applied to Affigel column (1 ml bed volume) previously equilibrated with 0.25 M acetic acid followed by 0.1 mM N-[2-hydroxyethyl]piperazine-N″-2-ethanesulfonic acid (HEPES)/0.1 mM NaCl wash buffer (pH 8.5). cAMP is washed off column with HEPES/NaCl, 5″-AMP is eluted in 4 ml volumes with 0.25 M acetic acid. 1 ml of eluate is counted in 3 ml scintillation fluid for 1 minute ([3H].

[0064] Substrate conversion=(cpm positive control×4)/total activity. Conversion rate must be between 3 and 15% for experiment to be valid.

[0065] % Inhibition—1-(eluted cpm—background cpm/control cpm—bkgd cpm)×100.

[0066] IC₅₀ values are generated by linear regression of inhibition titer curve (linear portion); and are expressed in μM.

TNF

[0067] The ability of the compounds of formula I and the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay:

[0068] Peripheral blood (100 mls) from human volunteers is collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolated by Ficol/Hypaque and washed three times in incomplete Hanks' balanced salt solution (HBSS). Cells are resuspended in a final concentration of 1×10⁶ cells per ml in prewarmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1×10⁶ cells in 1.0 ml in 24-well plates. The cells are incubated at 37° C. (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gently washing. Test compounds (10 μl) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. Lipopolysaccharide (LPS) (10 μl) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37° C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (R&D Quantikine Kit). IC₅₀ determinations are made for each compound based on linear regression analysis.

[0069] For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of the compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter also referred to as the active compounds of the present invention) are generally in the range of from 0.1-400 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.1 to 60 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 40 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1% (w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.

[0070] For administration to humans for the inhibition of TNF, a variety of conventional routes can be used including oral, parenteral and topical administration routes. In general, the active compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. The compound of formula I can also be administered topically in an ointment or cream in concentrations of about 0.5% to about 1%, generally applied 2 or 3 times per day to the affected area. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

[0071] For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovales either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances; for example, enough salts or glucose to make the solution isotonic.

[0072] The present invention is illustrated by the following preparations and examples, but it is not limited to the details thereof. In the following preparations and examples, the term “t-BOC” represents a t-butoxycarbonyl group, and the symbol “Bn” represents a benzyl group.

PREPARATION 1 O-Benzyl-α-N-t-BOC-Glycine Hydroxamate

[0073] To a mixture of 3.0 g (0.017 mol) of α-N-(t-butoxycarbonyl)glycine, 2.7 g (0.017 mol) of O-benzylhydroxylamine hydrochloride, and 60 ml of CH₂Cl₂ was added 3.6 ml (2.6 g, 0.026 mol) of triethylamine followed by 5.0 g (0.026 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The suspension was stirred for 16 h at room temperature under N₂. The clear mixture was evaporated and the semi-solid residue was dissolved in 300 ml of EtOAc, washed with aqueous 1N HCl solution (2×200 ml), saturated aqueous NaHCO₃ solution (2×200 ml), and dried over MgSO₄. Removal of the drying agent by filtration and evaporation of the solvent afforded 4.3 g (90%) of the title compound as a clear oil. R_(f) 0.2 (2:3 EtOAc-hexane).

[0074]¹H-NMR (CDCl₃): δ 1.37 (9H, s), 2.62 (2H, br s), 4.82 (2H, s), 5.10 (1H, br s), 7.23-7.35 (5H, m), 8.89 (1H, br s).

PREPARATION 2 O-Benzyl-α-N-[(3-Cyclopentyloxy-4-Methoxy)Benzoyl]Glycine Hydroxamate

[0075] A mixture of 4.3 g of the compound of Preparation 1 and 20 ml of a 4M HCl solution in dioxane was stirred for 4 hr at room temperature protected from atmospheric moisture with a CaCl₂ tube. At this time TLC analysis showed complete consumption of starting materials and the solvent was evaporated to give 3.2 g of O-benzyl-glycine hydroxamate hydrochloride as a gummy solid.

[0076] To a mixture of 1.35 g (6.35 mmol) of the solid above, 1.50 g (6.35 mmol) of 3-cyclopentyloxy-4-methoxybenzoic acid, and 60 ml of CH₂Cl₂ was added 1.33 ml (966 mg, 9.53 mmol) of triethylamine followed by 1.83 g (9.63 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring for 16 hr at room temperature, the mixture was evaporated and the residue was dissolved in 150 ml of EtOAc, washed with aqueous 1N HCl solution (2×75 ml), saturated aqueous NaHCO₃ solution (2×75 ml), and dried over MgSO₄. The drying agent was removed by filtration, the filtrate was evaporated, and the residue was purified by flash chromatography (75 g of silica gel) using a 4:1 EtOAc-hexane eluant to give 773 mg (30%) of the title compound as a foam; R_(f) 0.35 (EtOAc).

[0077]¹H-NMR (DMSO-d⁶): δ 1.44-2.00 (9H, m), 3.75 (5H, br s), 4.70-4.82 (1H, m), 4.74 (2H, s), 6.95 (1H, d, J=8), 7.22-7.46 (7H, m), 8.54 (1H, m).

PREPARATIONS 3-16

[0078] The following compounds, having a structure of formula 11, were prepared in accord with the procedure of Preparation 1 except using as starting materials an α-N-t-BOC-AA-OH amino acid, wherein AA is as defined in Table 1, in place of α-N-t-BOC-glycine. TABLE 1 II α-N-t-BOC-AA-NHOBn Preparation Melting Point No. AA (° C.) Data 3

103-105 ¹H-NMR(CDCl₃): δ1.43(9H, s), 2.91(3H, s), 3.91(2H, br s), 3.92 (2H, s), 7.36-7.43(5H, m) 4

101-103 ¹H-NMR(CDCl₃): δ1.31(3H, d, J=8), 1.40(3H, s), 3.90-4.03(1H, m), 4.80-4.92(1H, br s), 4.89 (2H, s), 7.25-7.36(5H, s), 8.78-8.96(1H, br s) 5

102-104 ¹H-NMR(CDCl₃): δ1.29(3H, d, J=8), 1.38(9H, s), 3.88-4.01(1H, m), 4.78-4.92(1H, br s), 4.85 (2H, s), 7.20-7.36(5H, s), 8.75-9.00(1H, br s) 6

107-109 ¹H-NMR(CDCl₃): δ1.44(9H, s), 2.21-2.65(2H, m), 2.41(2H, q, J=7), 4.76-5.07(3H, m), 7.33-7.44(5H, m), 8.27(1H, br s) 7

134-136 ¹H-NMR(CDCl₃): δ1.36(9H, s), 1.42(6H, s), 4.66(1H, br s), 4.86 (2H, s), 7.26-7.37(5H, m), 9.30 (br s) 8

— ¹H-NMR(CDCl₃): δ1.37(9H, s), 4.60-4.76(1H, m), 4.85(2H, s), 5.56-5.64(1H, br s), 5.26-5.7.35 (5H, m), 8.97(1H, br s) 9

oil ¹H-NMR(CDCl₃): δ0.86(6H, d, J=7), 1.37(9H, s), 1.50-1.67(3H, m), 3.80-3.90(1H, m), 4.70-4.81 (1H, m), 4.85(2H, s), 7.25-7.36 (5H, m), 8.70(1H, br s) 10

oil ¹H-NMR(CDCl₃): δ0.80(6H, d, J=7), 1.31(9H, s), 1.44-1.60(3H, m), 3.76-3.88(1H, m), 4.68-4.80 (1H, m), 4.79(2H, s), 7.20-7.30 (5H, m), 8.77(1H, br s) 11

127-129 ¹H-NMR(CDCl₃): δ0.93(6H, d, J=7), 1.43(9H, s), 1.99-2.12(1H, m), 3.62-3.72(1H, m), 4.91(2H, s), 4.98-5.10, 7.30-7.42(5H, m), 8.80(1H, s) 12

128-130 ¹H-NMR(CDCl₃): δ0.93(6H, d, J=7), 1.44(9H, s), 1.99-2.13(1H, m), 3.60-3.73(1H, m), 4.92(2H, s), 4.98-5.10(1H, m), 7.30-7.43 (5H, m), 8.77(1H, br s) 13

90-92 ¹H-NMR(CDCl₃): δ1.40(9H, s), 2.86-3.00(1H, br s), 3.52-3.64 (1H, m), 3.92-4.10(2H, m), 3.89 (2H, s), 5.44-5.56(1H, m), 7.26-7.38(5H, m), 9.20(1H, br s) 14

84-86 ¹H-NMR(CDCl₃): δ1.40(9H, s), 3.05-3.15(1H, br s), 3.50-3.63 (1H, m), 3.92-4.03(2H, m), 3.89 (2H, s), 5.46-5.56(1H, m), 7.28-7.40(5H, m), 9.33(1H, br s) 15

186-87 Anal. Calculated formula C₁₇H₂₄N₂O₄: C, 63.96; H, 7.80; N, 8.87. Found: C, 63.96; H, 7.80; N, 8.87 16

187-188 Anal. Calculated formula C₁₇H₂₄N₂O₄: C, 63.96; H, 7.80; N, 8.87. Found: C, 63.91; H, 7.76; N, 8.94

PREPARATION 17 O-Benzyl-(3-Cyclopentyloxy-4-Methoxy)Benzoylhydroxamate

[0079] Following the procedure of Preparation 1 except substituting 3-cyclopentyloxy-4-methoxybenzoic acid for α-N-t-BOC-glycine, the title compound was prepared as fluffy white crystals after recrystallization from hexane/CH₂Cl₂, m.p. 120.5-121° C.

[0080] Anal. Calculated formula C₂₀H₂₃NO₄: C, 70.36; H, 6.79; N, 4.10. Found: C, 70.31; H, 6.97; N, 4.43.

PREPARATION 18 t-Butyl-α-N-Benzyloxy-α-N-[(3Cyclopentyloxy-4-Methoxy)Benzoyl]Glycinate

[0081] To a dry 25 ml 3-necked flash under N₂ was placed 77.8 mg (1.62 mmol) of 50% NaH in mineral oil which was subsequently washed with hexane. The bare hydride was suspended in 1 ml of tetrahydrofuran (hereinafter “THF”) and treated dropwise with a solution of 504 mg (1.48 mmol) of the compound of Preparation 17 in 4 ml of THF. After the H₂ evolution had ceased and the mixture became clear, 261 μl (315 mg, 1.62 mmol) of t-butyl acetate was added. An additional 447 μl of t-butyl acetate was added 2 hours later. After stirring for 16 hours at room temperature, the mixture was diluted with 50 ml of ether, washed with H₂O (1×30 ml), 1N NaOH solution (3×30 ml), dried (MgSO₄), and evaporated to 846 mg of an oil.

[0082] Purification of the oil by flash chromatography (70 g of silica gel) using 20% EtOAc-hexane as eluant gave 476 mg of an oil which spontaneously crystallized. Trituration in hexane gave 392 mg a white solid, m.p. 87-89° C., which was recrystallized from hexane to yield 302 mg of the title compound as white needles, m.p. 88-90° C.

[0083] Anal. Calculated formula C₂₆H₃₃NO₈: C, 68.55; H, 7.30; N, 3.07. Found: C, 68.84; H, 7.57; N, 3.02.

PREPARATION 19 O-Benzyl-α-N-Benzyloxy-α-N-[(3-Cyclopentyloxy-4-Methoxy)Benzoyl]Glycine Hydroxamate

[0084] A mixture of 1.64 g (4.11 mmol) of the compound of Preparation 18 and 20 ml of trifluoroacetic acid was stirred at room temperature for 45 min using a CaCl₂ drying tube. The mixture was evaporated and the residue was dissolved in 100 ml of ether, washed with H₂O (3×76 ml), brine (1×75 ml), dried (MgSO₄), and evaporated to give 1.42 g of α-N-benzyloxy-α-N-[3-cyclopentyloxy-4methoxy)benzoyl]glycine,

[0085]¹H-NMR (CDCl₃): δ 1.52-1.97 (8H, m), 3.88 (3H, s), 4.50 (2H, s), 4.68-4.75 (1H, m), 4.78 (2H, s), 6.84 (1H, d, J=8), 7.12-7.42 (7H, m), 9.02 (1H, br s).

[0086] The title compound was prepared as a foam in analogy to the procedure of Preparation 1 substituting the above acid for α-N-(t-butoxycarbonyl)glycine.

[0087]¹H-NMR (CDCl₃): δ 1.48-1.95 (8H, m), 3.88 (3H, s), 4.38 (2H, s), 4.58-4.68 (1H, m), 4.69 (2H, s), 4.93 (2H, s), 5.83 (1H, d, J=8), 7.07-7.16 (2H, m), 7.23-7.42 (10H, m), 9.27 (1H, s).

PREPARATIONS 20-33

[0088] The following compounds, having the structure of formula III, were prepared in accord with the procedure of Preparation 2 except using as starting material the compounds from the indicated Preparations in place of the compound of Preparation 1. TABLE 2 III

Starting Material - Compound Of Melting Preparation Preparation Point No. AA No. (° C.) Data 20

 3 oil ¹H-NMR(CDCl₃): δ1.50-1.95(8H, m), 3.07 (3H, s), 3.85(3H, s), 3.95(2H, s), 4.68-4.78 (1H, m), 4.91(2H, s), 6.79(1H, d, J=8), 6.84-7.40(7H, m), 9.44(1H, br s) 21

 4 161-163 Anal. Calculated formula C₂₃H₂₈N₂O₅: C, 66.97; H, 6.84; N, 6.79. Found: 66.77; H, 7.02; N, 6.87 22

 5 163-165 ¹H-NMR(DMSO-d⁵): δ1.31(3H, d, J=7), 1.50-1.96(8H, m), 3.82(3H, s), 4.35(1H, br t), 4.81 (2H, s), 4.82-4.90(1H, m), 7.21(1H, d, J=8), 7.32-7.56(7H, m), 8.39 (1H, d, J=7) 23

 6 148-149 Anal. Calculated formula C₂₃H₂₈N₂O₅: C, 66.97; H, 6.84; N, 6.79. Found: 66.58; H, 7.12; N, 6.74 24

 7 135-137 Anal. Calculated formula C₂₄H₃₀N₂O₅: C, 67.58; H, 7.09; N, 6.57. Found: C, 67.31; H, 6.68; N, 6.80 25

 8 Oil ¹H-NMR(CDCl₃); δ1.46-1.96(8H, m), 3.85 (3H, s), 4.68-4.76(1H, m), 4.87(2H, s), 4.35-4.45(1H, m), 6.80(1H, d, J=8), 7.10(1H, d, J=8), 7.18-7.38(6H, m), 9.89(1H, s) 26

 9 140-142 Anal. Calculated formula C₂₆H₃₄N₂O₅: C, 68.70; H, 7.54; N, 6.16. Found: C, 68.36; H, 7.69; N, 6.37 27

10 142-144 Anal. Calculated formula C₂₆H₃₄N₂O₅: C, 68.70; H, 7.54; N, 6.16. Found: C, 68.46; H, 7.72; N, 6.31 28

11 173-176 Anal. Calculated formula C₂₅H₃₂N₂O₅: C, 68.16; H, 7.32; N, 6.36. Found: C, 67.88; H, 7.30; N, 6.48 29

12 173-176 Anal. Calculated formula C₂₅H₃₂N₂O₅: C, 68.16; H, 7.32; N, 6.36. Found: C, 67.88; H, 7.33; N, 6.50 30

13 122-124 Anal. Calculated formula C₂₃H₂₈N₂O₆.1/4H₂O: C, 63.74; H, 6.60; N, 6.47. Found: 63.37; H, 7.02; N, 6.83 31

14 144-148 Anal. Calculated formula C₂₃H₂₈N₂O₆.1/4H₂O: C, 63.74; H, 6.60; N, 6.47. Found: 63.73; H, 6.56; N, 6.52 32

15 foam ¹H-NMR(DMSO-d⁶): δ1.41-2.16(12H, m), 3.40-3.63(2H, m), 3.75 (3H, s), 4.05-4.28(1H, m), 4.37-4.63(1H, m), 4.75(2H, s), 6.80-7.38 (8H, m), 8.25(1H, s) 33

16 foam ¹H-NMR(DMSO-d⁶): δ1.42-2.10(12H, m), 3.36-3.58(2H, m), 3.71 (3H, s), 4.03-4.25(1H, m), 4.35-4.58(1H, m), 4.70(2H, s), 6.76-7.35 (8H, m), 8.20(1H, s)

PREPARATION 34 N-[(3-Cyclopentyl-4-Methoxy)Benzoyl]Glycine Benzyl Ester

[0089]

[0090] To a mixture of 0.500 g (2.12 mmol) of 3-cyclopentyl-4methoxybenzoic acid and 0.470 g (2.33 mmol) of glycine benzyl ester hydrochloride in 20 ml of CH₂Cl₂ was added 0.410 g (2.12 mmol) of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride followed by 0.236 g (2.33 mmol) of triethylamine. The mixture was stirred for 16 hours at room temperature.

[0091] The solvent was evaporated and the residue was diluted with water (150 ml) and extracted with ether (2×150 ml). The combined ether extracts were washed with aqueous 1N HCl (1×150 ml), saturated aqueous NaHCO₃, dried (MgSO₄), and evaporated to 940 mg of a white solid. Purification by flash chromatography (55 g of silica gel) using a 3:7 EtOAc:hexane eluant afforded 518 mg of the title compound, mp 108-109° C.

[0092]¹H NMR (CDCl₃): δ 1.40-1.95 (8H, m), 3.85 (3H, s), 4.24 (2H, d, J=5), 4.70-4.80 (1H, m), 5.20 (2H, s), 6.50 (1H, br s), 6.83 (1H, d, J=8), 7.10-7.40 (7H, m).

EXAMPLE 1 α-N-[(3-Cyclopentyloxy-4-Methoxy)Benzoyl]Glycine Hydroxamic Acid

[0093] A mixture of 770 mg of the compound of Preparation 2, 70 mg of Pd(OH)₂, and 50 ml of methanol was hydrogenated at 40 psi on a Parr Shaker apparatus for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated to a solid which was triturated in ether to afford 510 mg of the title compound, m.p. 160-161° C.

[0094] Anal. Calculated formula C₁₅H₂₀N₂O: C, 57.54; H, 6.55; N, 8.95. Found, C, 57.48; H, 6.51; N, 8.74.

EXAMPLES 2-16

[0095] The compounds of Examples 2-16, having the structure of formula IV, were prepared in accord with the procedure described in Example 1 except using as starting material the compounds of Preparations 19-33 rather than the compound of Preparation 2. TABLE 3 IV

Starting Material - Compound Of Example Preparation Melting Point No. AA No. (° C.) Data  2

19 80-105(dec.) Anal. Calculated formula C₁₅H₂₀N₂O₆: C, 55.55; H, 6.22; N, 8.64. Found: C, 55.40; H, 6.61; N, 8.44  3

20 132-142 (dec.) Anal. Calculated formula C₁₆H₂₂N₂O₅: C, 59.62; H, 6.88; N, 8.69. Found: C, 59.77; H, 7.10; N, 8.49  4

21 117-130 (dec.) Anal. Calculated formula C₁₆H₂₂N₂O₅: C, 59.62; H, 6.88; N, 8.69. Found: C, 59.82; H, 6.99; N, 8.74  5

22 152-154 Anal. Calculated formula C₁₆H₂₂N₂O₅.1/4H₂O: C, 58.78; H, 6.94; N, 8.57. Found: C, 58.72; H, 7.03; N, 8.56  6

23 153-156 Anal. Calculated formula C₁₆H₂₂N₂O₅: C, 59.62; H, 6.88; N, 8.69. Found: C, 59.37; H, 6.59; N, 8.83  7

24 104-107 Anal. Calculated formula C₁₇H₂₄N₂O₅.1/2H₂O: C, 59.06; H, 7.24; N, 8.11. Found: C, 59.14; H, 7.59; N, 7.83  8

25 155-147 LSI-MS(m/e); 377(M⁺), 344, 276, 219  9

26 150-153 Anal. Calculated formula C₁₉H₂₈N₂O₅: C, 62.62; H, 7.74; N, 7.69. Found: C, 62.95; H, 8.14; N, 7.71 10

27 151-154 ¹H-NMR(DMSO-d⁶): δ0.89(3H, d, J=7), 0.94 (3H, d, J=7), 1.43-2.03 (11H, m), 3.80(3H, s), 4.55(1H, br t), 4.82-4.98 (1H, m), 7.01(1H, d, J=8), 7.48(1H, s), 7.55 (1H, d, J=8), 8.22 and 8.32(1H total, two d, J=9), 8.85(0.5H, s), 10.72(0.5H, s) 11

28 166-167 Anal. Calculated formula C₁₈H₂₆N₂O₅.1/2H₂O: C, 60.10; H, 7.51; N, 7.80. Found: C, 60.21; H, 7.70; N, 7.87 12

29 183-186 Anal. Calculated formula C₁₈H₂₆N₂O₅.1/4H₂O: C, 60.86; H, 7.47; N, 7.89. Found: C, 60.64; H, 7.70; N, 7.76 13

30 149-152 Anal. Calculated formula C₁₆H₂₂N₂O₆.3/4H₂O: C, 54.56; H, 6.68; N, 7.96. Found: C, 54.17; H, 6.81; N, 8.15 14

31 143-147 Anal. Calculated formula C₁₆H₂₂N₂O₆.1/4H₂O: C, 55.99; H, 6.56; N, 8.17. Found: C, 55.67; H, 6.96; N, 7.87 15

32 116-120 (dec.) Anal. Calculated formula C₁₈H₂₄N₂O₅.1/2H₂O: C, 60.49; H, 7.00; N, 7.84. Found: C, 60.75; H, 7.20; N, 7.81 16

33 117-121 ¹H-NMR(DMSO-d⁶): δ1.51-2.22(10, m), 3.50 (1H, br t), 3.62(1H, br t), 3.80(3H, s), 4.33(1H, br t), 4.78-4.86(1H, m), 6.90(1H, br s), 7.00(1H, d, J=8), 7.12(1H, s), 7.15(1H, d, J=8), 11.2 (1H, s)

EXAMPLE 17 N-[(3-Cyclopentyl-4-Methoxy)Benzoyl]Glycine

[0096]

[0097] The compound of Example 17 was prepared in accord with the procedure described in Example 1 except using as starting material the compound of Preparation 34 rather than the compound of Preparation 2; m.p. 156-158° C.

[0098] Anal. Calculated formula C₁₅H₁₉NO₅.1/4H₂O: C, 60.04; H, 6.55; N, 4.70. Found: C, 60.07; H, 6.59; N, 4.56. 

1. A compound of formula

or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of methyl, ethyl, difluoromethyl and trifluoromethyl; R² is (C₁-C₆)alkyl, (C₃-C₇)alkoxy(C₂-C₄)alkyl, phenoxy(C₂-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₆-C₉)polycycloalkyl, phenyl(C₁-C₈)alkyl or indanyl wherein the alkyl portion of said R² groups is optionally substituted with one or more fluorine atoms and the aryl portion of said R² groups is optionally substituted with one or more substituents independently selected from the group consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy and halogen; AA is (AA-1) or (AA-2) wherein: (AA-1) is

 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, trifluoromethyl, (C₁-C₆)alkyl, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CONH₂, —(CH₂)_(n)phenyl, —(CH₂)_(x)OH, and —(CH₂)_(x)NH₂, wherein x ranges from 1 to 5, n ranges from O to 5, R⁵ is hydrogen, OH or (C₁-C₆)alkyl, and m ranges from 0 to 5; and (AA-2) is

 wherein p ranges from 1 to 4; and Y is NHOH or OH.
 2. The compound of claim 1 wherein R¹ is methyl.
 3. The compound of claim 1 wherein R² is cyclopentyl.
 4. The compound of claim 1 wherein AA is (AA-1) and R³ is selected from the group consisting of hydrogen, methyl, trifluoromethyl and hydroxymethyl.
 5. The compound of claim 1 wherein AA is (AA-1) and R⁴ is hydrogen.
 6. The compound of claim 1 wherein AA is (AA-1) and R⁵ is hydrogen.
 7. The compound of claim 1 wherein AA is (AA-1) and m is
 0. 8. The compound of claim 1 wherein AA is (AA-2) and p is
 3. 9. The compound of claim 1 wherein Y is NHOH.
 10. A compound according to claim 1 that is selected from the group consisting of α-monofluoromethyl-α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid; α-difluoromethyl-α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid; α-ethyl-α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid; α-propyl-α-N-[(3cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid; α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]-D-cystine hydroxamic acid; α-trifluoromethyl-α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid; α-N-[(3cyclopentyloxy-4-methoxy)benzoyl]-D-serine hydroxamic acid; α-N-[(3cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid; and, α-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]-D-alanine hydroxamic acid.
 11. A pharmaceutical composition for inhibiting phosphodiesterase type IV or inhibiting the production of tumor necrosis factor in a mammal comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
 12. A pharmaceutical composition for treating a condition or disease selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis, AIDS, septic shock and other conditions or diseases that respond to the inhibition of PDE type IV or the inhibition of the production of TNF in a mammal, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
 13. A method of inhibiting PDE type IV or inhibiting the production of TNF in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 1. 14. A method of treating a condition or a disease selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis, AIDS, septic shock and other conditions or diseases that respond to the inhibition of PDE type IV or the inhibition of the production of TNF in a mammal, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 1. 